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REVIEW JURNAL air atau lipofilik

(BCS di kelas II
Solubility and Dissolution Enhancement of Meropenem by Nano dan IV) .
Suspension Approach Penyerapan obat
yang sulit larut
tidak dapat
diselesaikan
dalam waktu di
situs penyerapan
karena laju
disolusi lambat
dan generasi
gradien
konsentrasi
rendah di saluran
pencernaan yang
mengarah ke
kemungkinan
dekomposisi
lambung obat
karena waktu
tinggal lebih
lama
gastrointestinal
dan
DISUSUN OLEH bioavailabilitas
rendah.
Kelarutan dapat
SANIA SYARIF FATUNNISA 11161106 dinyatakan
dalam satuan
SRI OKTAVIANI 11161112 konsentrasi,
molalitas, fraksi
ANDRIASTI SALSABILA 11161124 mol, rasio mol,
dan unit lainnya.
Meropenem
adalah antibiotik
spektrum luas
carbapenem6
dan
SEKOLAH TINGGI FARMASI BANDUNG diklasifikasikan
sebagai Obat
2018 kelas IV BCS7
berarti memiliki
kelarutan rendah
PENDAHULUAN dan
permeabilitas
Rute oral adalah rute yang paling umum dan populer untuk pemberian obat. Lebih rendah. Berbagai
dari 40% dari obat-obatan sintesis kimia baru adalah senyawa yang tidak larut dalam pendekatan telah
dipelajari untuk mengatasi masalah kelarutan dan bau nafas yang tidak
menyenangkan dari bahan farmasi aktif milik BCS - II dan IV. Meropenem
memberikan aksinya dengan menembus sel bakteri dengan mudah dan mengganggu
sintesis komponen dinding sel vital, yang menyebabkan kematian sel. Oleh karena
itu, ada kebutuhan untuk meningkatkan kelarutan dan pembubaran obat dalam
cairan tubuh untuk meningkatkan bioavailabilitasnya.
BAHAN DAN METODE Zeta potensial
sangat dapat
mempengaruhi
I. METODE PERSIAPAN stabilitas
nanosuspensions.
Metode penguapan pelarut emulsifikasi Untuk
nanosuspension
Nanosuspension Meropenem disiapkan dengan teknik penguapan pelarut
stabilitas
emulsifikasi. Obat (400 mg) dan HPMC (100 mg) dilarutkan dalam 10 ml DCM dan
elektrostatik
metanol (pelarut) (5 ml) pada suhu kamar. Larutan tersebut dituangkan ke dalam
harus memiliki
jumlah tetap (50 ml) non-pelarut (Air) yang mengandung SLS (100 mg) sebagai
potensi zeta
penstabil surfaktan pada suhu yang sama. Tundukkan campuran tersebut ke
minimum ±
gelombang ultrasonik selama 15 menit diikuti dengan pengadukan mekanis selama
30mV. Untuk
20 menit. Nanosuspension yang disiapkan dibiarkan diaduk selama 1 jam pada suhu
stabilisasi
kamar untuk menguapkan pelarut organik. Centrifuge dispersi dan mengumpulkan
elektrostatik dan
nanosuspension. Formulasi yang berbeda disiapkan dengan mengubah konsentrasi
sterik gabungan
polimer.
minimum ±
II. STUDI EVALUASI 20mV
diperlukan.
Nanosuspension disiapkan dan dievaluasi untuk berbagai karakteristik.
Potensi zeta
Studi Kelarutan nanosuspension
diukur
Studi kelarutan pada nanosuspensions dilakukan dengan menambahkan jumlah kelebihan menggunakan
serbuk nanosuspensi kering ke 10 ml dapar fosfat pH 6,8. Labu tersegel diagitasi pada Malvern
pengocok orbital selama 12 jam pada 37 ° C. Kemudian sampel disentrifugasi pada 8000
Zetasizer ZS200
rpm selama 10 menit dengan centrifuge kecepatan tinggi (REMI R-8C, REMI laboratory
pada 25 ± 0,5ºC.
Instruments, Bombay.) Dan solusi disaring menggunakan 0,45μ filter membran berpori
sebelum analisis U.V pada 293 nm. VI. KON
TEN
III. KECANDUAN OBAT-STUDI KOMPATIBILITAS
OBA
Karakteristik solid state obat diketahui memiliki pengaruh signifikan terhadap T
parameter kelarutan. Sampel untuk analisis disiapkan dengan mencampur rasio
Nanosuspensi
50:50 obat dan eksipien. Kemudian dianalisis oleh DSC (METTLER TOLEDO
yang setara
822E peralatan menggunakan perangkat lunak E star). Sampel diambil secara
dengan 40 mg
terpisah dalam wadah aluminium ditusuk dengan kapasitas 40 µl dan dievaluasi
obat dipindahkan
dalam suhu mulai dari 25250 ºC pada pemanasan 10 º C / menit dengan aliran
ke tabung
nitrogen. Kompatibilitas eksipien obat dipelajari lebih lanjut dengan spektroskopi
volumetrik (25
FTIR (BRUKER Alpha, Bombay) di wilayah bilangan gelombang 400 hingga 4000
ml) dilarutkan
Cm-1.
dan dibuat
IV. UKURAN PARTIKEL hingga 25 ml
dengan metanol.
Ukuran partikel nanosuspensions diukur menggunakan Malvern Zetasizer ZS200. Kemudian
Ukuran partikel memiliki hubungan terbalik dengan kelarutan. pengenceran
yang lentur
dibuat dengan
buffer fosfat pH
V. ZETA POTENSIAL 6,8 dan konten
obat dianalisis
terhadap kosong dengan spektrofotometer UV pada 293 nm.

VII. EFISIENSI PELEPASAN

Nanosuspensions yang baru disiapkan disentrifugasi pada 2000 rpm selama 20 menit
pada suhu 25 ° C menggunakan centrifuge kecepatan tinggi. Jumlah obat yang
dimasukkan diukur dengan mengambil absorbansi dari 25 ml larutan supernatan
yang tepat diencerkan pada 293 nm menggunakan spektrofotometer UV terhadap
nanosuspensi kosong / kontrol. Efisiensi entrapsi dihitung dengan menggunakan
rumus
sebagai
berikut:

VIII. PEMERIKSAAN MORFOLOGIS

Pemeriksaan morfologi dari nanosuspension disiapkan dipelajari dengan


menundukkan analisis SEM.

IX. SCANNING ELECTRON MICROSCOPY (SEM)

Morfologi partikel padat obat murni dan nanosuspensi dipelajari dengan


menggunakan analisis SEM. Setetes nanosuspensi obat tersebar dan dipasang pada
stub aluminium yang ditutupi dengan lamella kaca, udara kering di bawah vakum
dan kemudian diperiksa.

X. EFISIENSI DISOLUSI

Efisiensi pelarutan (DE30min) nanosuspension pada 30 menit dihitung dari data


studi disolusi in vitro dengan menggunakan rumus berikut.
XI. STUDI DISOLUSI IN-VITRO

Studi disolusi in-vitro dilakukan dengan menggunakan alat USP IIRotating paddle
(Electrolab-TDT-101, Bombay) menggunakan dapar fosfat pH 6,8 pada kecepatan
50 rpm dan suhu 37 ± 0,5 ° C. Ditransfer 900 mL media pembubaran ke masing-
masing pembuluh. Setelah mencapai suhu yang diperlukan nanosuspension
ditransfer setara dengan 40 mg obat ke masing-masing pembuluh pembubaran dan
segera mulai. Pada titik waktu tertentu, menarik 5 ml sampel dari masing-masing
pembuluh pembubaran. Filter solusinya melalui filter membran 0,45 µm.
Pertahankan kondisi sink dengan menambahkan 5 ml buffer segar ke dalam setiap
kapal pembubaran segera. Analisis kuantitatif meropenem dilakukan menggunakan
spektrofotometer UV (Shimatzu UV-1800) pada 293 nm.

XII. KINETIKA RILIS IN-VITRO

Model matematika digunakan untuk mengevaluasi kinetika dan mekanisme


pelepasan obat dari nanosuspensions. Model yang paling sesuai dengan data rilis
dipilih berdasarkan nilai koefisien korelasi (r2) dalam berbagai model. Eksipien
meningkatkan laju disolusi obat dengan meningkatkan luas permukaan obat aktif
dalam kontak dengan medium disolusi. 15 Nilai koefisien korelasi dari berbagai
model kinetik ditunjukkan pada Tabel 2. Studi stabilitas dilakukan dengan
menyimpan nanosuspensi pada kondisi dipercepat sesuai pedoman ICH.
HASIL DAN DISKUSI Efisiensi entrapsi
dari 10 formulasi
I. KELARUTAN dihitung.
Studi kelarutan dilakukan untuk semua nanosuspension. Formulasi F8 menunjukkan Efisiensi
kelarutan tinggi bila dibandingkan dengan formulasi lain dan itu jelas menunjukkan jebakan% dari
bahwa peningkatan kelarutan obat dalam bentuk nano bila dibandingkan dengan semua formulasi
obat murni, mungkin karena penurunan ukuran partikel dan peningkatan solubilisasi. ditemukan pada
kisaran 52,5%
II. KECANDUAN OBAT- KOMPATIBILITAS hingga 92,6%.
Hasil ukuran
Studi DSC dilakukan untuk campuran obat dan obat-obatan, ditemukan puncak
partikel, potensi
endotermik tajam pada 129ºC pada Gambar 1, yang disebabkan oleh sifat kristal
zeta, kandungan
obat. Ketika DSC thermo gram campuran obat eksipien (gambar 1) dibandingkan
obat, kelarutan,
dengan obat, diamati bahwa sedikit pergeseran di puncak menuju suhu yang lebih
kandungan obat,
rendah adalah karena perubahan dalam keadaan fisik obat pada formulasi. DSC dan
dan efisiensi
studi FTIR (Gambar 2). ) membuktikan tidak adanya interaksi eksipien obat.
jebakan
III. ANALISIS UKURAN PARTIKEL ditunjukkan pada
Tabel 2.
Ukuran partikel nanosuspensions meropenem dari semua formulasi ditemukan
berada di kisaran 2,0-1652,4 nm. Batch F8 memiliki ukuran partikel kurang 2,0 nm VIII. STU
dibandingkan dengan formulasi lain dan partikel dalam distribusi seragam seperti DI
yang diilustrasikan pada Gambar 3. PEL
IV. ZETA POTENSIAL EPA
SAN
Potensi Zeta diukur dengan menggunakan Malvern Zetasizer ZS200. Dari hasil
IN-
semua batch, formulasi yang dioptimalkan F8 menunjukkan potensi zeta pada 25 ° C
VITR
adalah -28,3 mV, zeta potensial di bawah ± 30 mv menunjukkan stabilitas fisik yang
O
baik.19 Potensi Zeta dari nanosuspensionformulation dioptimalkan diberikan pada
DAN
Gambar 4.
EFISI
V. SCANNING ELECTRON MICROSCOPHY ENSI
DISO
Penampilan permukaan nanosuspensions dan bentuk dianalisis dengan scanning LUSI
Electron Microscope (SEM). Gambar 5 menunjukkan bentuk dan tampilan
permukaan nanosuspension yang dibuat dan ditemukan bulat dalam agregat longgar Hal ini terbukti
dengan tekstur permukaan yang halus. dari penelitian
pelepasan obat in
VI. KANDUNGAN OBAT vitro bahwa,
meropenem
Isi obat dianalisis untuk 10 formulasi dan hasilnya diberikan pada Tabel 2. Isi obat
murni
dari semua formulasi ditemukan berada di kisaran 90,24% hingga 95,62% dan nilai-
menunjukkan
nilai ini berada dalam batas farmakope.
8,6% pelepasan
obat pada akhir
60 menit itu
mungkin
disebabkan sifat
VII. EFISIENSI ENTRAPSI
hidrofobik dan
kristalnya yang
lebih tinggi.
Sedangkan formulasi nanosuspensi menunjukkan lebih dari 50% pelepasan obat
pada akhir 60 menit. Nanosuspension yang dioptimalkan (F8) menunjukkan
pelepasan obat 97,7% pada akhir 60 menit. Profil disolusi obat murni dan
nanosuspensi ditunjukkan pada Gambar 6. Efisiensi pelarutan semua formulasi
dihitung. Efisiensi disolusi formulasi dioptimalkan cukup tinggi (92,6%) bila
dibandingkan dengan formulasi lain. Dari Tabel 2, ditemukan bahwa nilai r2
pesanan pertama lebih besar dari nilai pesanan nol. Profil kinetik dari nol dan urutan
pertama ditunjukkan pada Gambar 7. Oleh karena itu pelepasan obat dari
nanosuspensions mengikuti kinetika orde pertama, nilai koefisien korelasi model
Hixson Crowell lebih besar dari Higuchi kinetika (Tabel 2), menunjukkan pelepasan
obat berikut Hixson Crowell kinetika akar kubus. Oleh karena itu perubahan luas
permukaan ke volume dengan waktu bisa menjadi alasan yang mungkin untuk
peningkatan kelarutan dan pembubaran meropenam larut buruk pada nanonization.

IX. STUDI STABILITAS

Hasil studi stabilitas nanosuspensions menunjukkan bahwa tidak ada perubahan


yang signifikan sehubungan dengan berbagai parameter seperti ukuran partikel,
kadar air, potensi zeta, kelarutan dan pembubaran sebelum dan sesudah
penyimpanan untuk jangka waktu 6 bulan sesuai pedoman ICH. Oleh karena itu
nanosuspension ditemukan stabil pada suhu kamar normal.
KESIMPULAN

Metode penguapan pelarut emulsifikasi digunakan dalam pembuatan nanosuspensi


meropenem, obat yang sulit larut. Mengubah parameter operasi seperti waktu
sonication dan konsentrasi solubilizer dan stabilizer, berbagai formulasi
nanosuspensi dikembangkan untuk mendapatkan ukuran partikel dalam kisaran
nano. Rentang ukuran optimal diperoleh dengan nanosuspension yang mengandung
300 mg HPMC E 15, 150 mg SLS selama 25 menit waktu sonication. Kelarutan dan
disolusi meropenem meningkat secara signifikan dibandingkan dengan suspensi obat
murni. Pembubaran obat yang disempurnakan adalah karena penurunan ukuran
partikel serta hidrasi obat oleh polimer hidrofilik dan solubilizer. Kesimpulannya,
metode evaporasi pelarut emulsifikasi adalah pendekatan yang sederhana dan efektif
untuk menghasilkan partikel nanosized dari obat yang larut dalam air yang buruk.
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LAMPIRAN
J Young Pharm, 2017; 9(3): 429-435
Original Article
A multifaceted peer reviewed journal in the field of Pharmacy

www.jyoungpharm.org | www.phcog.net

Solubility and Dissolution Enhancement of Meropenem by


Nano Suspension Approach

Srinivasa Kumari Chirumamilla1, Uma Devi Padasala2, Haritha Aravally2, Lavakumar Vuppalapati3, Sowmya Cherukuri2*

OTPRI, Jawaharlal Nehru Technological University Ananthapur, Anathapuramu-Andhra Pradesh, INDIA.


1

Raghavendra Institute of Pharmaceutical Education and Research, K.R. Palli cross, Near S.K. University,
2 Anathapuramu, Andhra Pradesh, INDIA.

Arulmigu Kalasalingam College of Pharmacy, Anand Nagar, Krishnankoil, Srivilliputtur(Tk), Virudhunagar, Tamil Nadu 626126, INDIA.
3

ABSTRACT

nanosuspensions of meropenem could be successfully prepared and


Objective: To prepare and evaluate the suitable nanosuspensions of can be concluded that the nanosuspension formulation is a promising
Meropenem (BCS-IV drug) to increase its solubility and dissolution. approach to increase the solubility and dissolution of BCS-IV drugs
Methodology: The meropenem nanosuspensions were prepared by like meropenem.
emulsification solvent evaporation technique by applying ultrasonic en-ergy
through probe sonicator, where the organic phase of drug solution in
methanol was emulsified in aqueous phase containing hydroxy propyl
methyl cellulose as solubilizer and sodium lauryl sulphate as stabilizer. The
Key words: BCS-IV drug, Nanosuspensions, Solubility,
prepared nanosuspensions were characterised for particle size, zeta
Dissolution, Emulsification and Solvent Evaporation.
potential, surface morphology by SEM, drug excipient compatibil-ity by FTIR
and DSC and conducted in-vitro drug release studies. Re-sults: Results
showed that the prepared nanosuspensions were having particle size range
from 1 to 1000nm and the zeta potential from -10 to -20 mVs. Scanning
electron microscopic pictures revealed that the obtained nanosuspension Correspondence:
particles were spherical in shape with sur-face smoothness and in-vitro drug
release studies notified that the pre-pared nanosuspensions showed
increase in solubility and dissolution of meropenem when compared with
Sowmya Cherukuri, Head, Dept of Pharmaceutics, Raghavendra Institute
the pure form. Conclusion: The
of Pharmaceutical Education and Research, K.R. Palli cross, Near S.K.
University, Anathapuramu, Andhra Pradesh, INDIA.

Phone no: +91 9550334547

E-mail: drsowmyariper@gmail.com.

DOI: 10.5530/jyp.2017.9.84

soluble drugs cannot be completed within the time at absorption site due to
slow dissolution rate and generation of a low concentration gradient across
the gastrointestinal tract leading to possibilities of gas-tric decomposition
of drug due to longer gastrointestinal residence time and low
bioavailability.3 This type of drugs has always been a challeng-ing problem
INTRODUCTION to pharmaceutical scientists in formulating suitable dosage forms. 4
Solubility may be stated in units of concentration, molality, mole fraction,
mole ratio, and other units.5 Meropenem is a broad-spectrum carbapenem
Oral route is the most common and popular route for administration of antibiotic6 and classified as BCS class IV drug7 means hav-ing low
drugs.1 More than 40% of the new chemically synthesized drugs be-ing solubility and low permeability. Various approaches have be studied to
generated through drug discovery programmers are poorly water‐ soluble overcome the solubility issues and unpleasant breath odour of active
or lipophilic compounds (BCS in class II and IV). 2 The uptake of poorly pharmaceutical ingredients belongs to BCS – II and IV.8 Merope-nem
exerts its action by penetrating bacterial cells readily and interfer-ing with
the synthesis of vital cell wall components,9 which leads to cell death.
Hence, there is a need to increase its solubility and dissolution of drug in
the body fluids to increase its bioavailability.

MATERIAL AND METHODS


vate limited, Mumbai and other reagents and chemicals used in the
study are analytical grade.
Meropenem was obtained as gift sample from Aurobindo Pharma Ltd.
Hyderabad. Sodium lauryl sulphate [SLS], Hydroxy Propyl Methyl Cel-
lulose [HPMC-E-15] were purchased from the S.d. Fine Chemicals pri-
Method of Preparation

Emulsification solvent evaporation method

The Meropenem nanosuspensions were prepared by emulsification sol-


vent evaporation technique.10 Drug (400 mg) and HPMC (100 mg) was
dissolved in 10 ml of DCM and methanol (solvent) (5 ml) at room tem-
perature. This solution was poured into fixed amount (50 ml) of non-
sol-vent (Water) containing SLS (100 mg) as surfactant stabilizer at the
same temperature. Subject the mixture to ultrasonic waves for 15
minutes fol-lowed by mechanical stirring for 20 minutes. The prepared
nanosuspen-sion was left stirred for 1hr at room temperature to
evaporate the organic solvent. Centrifuge the dispersion and collected
the nanosuspension. Different formulations were prepared by changing
the concentration of polymer. The formulation details of meropenem
nanosuspensions are shown in Table 1.

Evaluation Studies

Prepared nanosuspensions were evaluated for various characteristics.

Solubility Studies

The solubility studies on nanosuspensions were performed by adding the


excess amount of dried nanosuspension powder to 10 ml phosphate buffer
of pH 6.8. The sealed flasks were agitated on an orbital shaker for

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Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017 429


Kumari et al.: Formulation and Evaluation of Meropenam Nano suspension

12 hr at 37°C. Then samples were centrifuged at 8000 rpm for 10 min


with high speed centrifuge (REMI R-8C, REMI laboratory
Instruments, Bombay.) and the solutions were filtered using 0.45µ
porous membrane filters before U.V analysis at 293 nm.

Drug – Excipient compatibility studies

The solid state characteristics of drug are known to have a significant The obtained DE30values are shown in Table2.
influence on the solubility parameter.11 Samples for analysis were pre-
pared by mixing 50:50 ratio of drug and excipients. Then analysed by DSC
(METTLER TOLEDO 822E equipment using E star software). The
samples were taken separately in a pierced aluminium crucible with a In-vitro dissolution studies
capacity of 40 µl and evaluated in the temperature ranging from 25-250ºC
at a heating of 10ºC/min with a stream of nitrogen. Drug excipient
compatibility is further studied by FTIR spectroscopy (BRUKER Alpha, In-vitro dissolution studies were performed by using USP apparatus II-
Bombay) in the wave number region of 400 to 4000 Cm-1. Rotating paddle (Electrolab-TDT-101, Bombay) using phosphate buffer pH
6.8 at 50 rpm speed and 37 ± 0.5°C temperature. Transferred 900 mL of
dissolution medium into each of the vessels. After attaining the required
temperature transferred nanosuspension equivalent to 40 mg of drug into
Particle Size
each of the dissolution vessel and start immediately. At specific time
points, withdrew 5 ml of the sample from each of the dissolution vessels.
The particle size of nanosuspensions were measured using Malvern Zeta- Filter the solution through 0.45 µm membrane filter. Maintain sink
condition by adding 5 ml of the fresh buffer into each dissolution vessel
sizer ZS200. The particle size has inverse relationship with solubility. 12
immediately. Quantitative analysis of meropenem was performed using UV
spectrophotometer (Shimatzu UV-1800) at 293 nm.

Zeta potential

Zeta potential can greatly influence the stability of nanosuspensions. 4For an


electrostatic stability nanosuspension should have zeta potential a
minimum of ±30mVs.For combined electrostatic and steric stabilization a Morphological examination
minimum of ±20mV is required. The zeta potential of nanosuspension was
measured using Malvern Zetasizer ZS200 at 25 ± 0.5ºC.
The morphological examination of the prepared nanosuspension was
studied by subjecting to SEM analysis.
Drug Content

Scanning electron microscopy (SEM)


The nanosuspensions equivalent to 40 mg of drug was transferred to a
volumetric flask (25 ml) dissolved and made up to 25 ml with
methanol. Then suiable dilutions were made with phosphate buffer of The solid particle morphology of pure drug and nanosuspension were
pH 6.8 and drug content was analyzed against blank by UV studied by using SEM analysis. A drop of drug nanosuspension was
spectrophotometer at 293 nm. dis-persed and mounted on aluminium stub covered with a glass
lamella, air dried under vacuum and then examined. The SEM photo
images were shown in Figure 5.
Entrapment efficiency

Dissolution efficiency
The freshly prepared nanosuspensions were centrifuged at 2000 rpm
for 20 min at 25°C temperature using high speed centrifuge. The
amount of incorporated drug was measured by taking the absorbance of Dissolution efficiency (DE30min) of nanosuspension at 30 min was calcu-
the ap-propriately diluted 25 ml of supernatant solution at 293 nm lated from the data of in vitro dissolution studies by using the following
using UV spectrophotometer against blank/control nanosuspensions.
Entrapment efficiency was calculated using the following formula:
formula.14
In vitro release kinetics Solubility

The mathematical models are used to evaluate the kinetics and mecha-
The solubility studies performed for all the nanosuspension. The
nism of drug release from the nanosuspensions. The model that best
formu-lation F8 showed high solubility when compared to other
fits the release data is selected based on the correlation coefficient (r2)
formulations and it was clearly showed that increased in solubility of
value in various models. Excipients increase drug dissolution rate by
drug in nano form when compared with pure drug, it may be due to
increas-ing active drug surface area in contact with the dissolution
decrease in par-ticle size and increased solubilisation.
medium.15 The correlation coefficient values of various kinetic models
are shown in Table 2.

Drug – Excipient compatibility studies


Stability studies were performed by storing the nanosuspensions at ac-
celerated conditions as per ICH guidelines.
The DSC studies were performed for drug and drug-excipient
mixture,it was found sharp endothermic peak at 129ºC in Figure 1,
which is due to the crystalline nature of drug. When DSC thermo gram
RESULTS AND DISCUSSION
of drug excipient mixture (figure 1) is compared with drug,it was
observed that slight shift in the peak towards lower temperature is due
to change in the physical state of drug on formulation.18 DSC and FTIR
Nano suspension approach is currently using method to enhance the
studies (Figure 2) proved the absence of drug excipient interactions.
solubility, dissolution rate there by bioavailability of poorly water sol-
uble drugs. Nano suspensions consist of poorly water soluble drugs
size below 1µm with or without any matrix material,16 which are
stabilized by surfactants and polymers.17 In the present study various Particle size analysis
meropenem nanosuspensions were prepared by emulsification solvent
evaporation technique. The formed nano formulations were almost
spherical and uniform in size. The particle size of meropenem nanosuspensions from all the formula-tions
was found to be in the range of 2.0 to 1652.4 nm. Batch F8 had less

430 Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017


Kumari et al.: Formulation and Evaluation of Meropenam Nano suspension

Figure 2: FTIR Spectras of pure meropenem and meropenem with


excipi-ents.
Figure 1: DSC Thermograms of pure meropenem and
meropenem with the excipients.

Figure 3: particle size of optimised nanosuspension formulation (F8).

particle size 2.0 nm as compared to other formulation and the particles Scanning Electron Microscopy
are in uniform distribution as illustrated in Figure 3.
The nanosuspensions surface appearance and shape were analyzed by
scanning Electron microscope (SEM). Figure 5 showed shape and sur-
Zeta potential face appearance of the prepared nanosuspension and were found to be
spherical in loose aggregates with surface smooth texture.

Zeta potential was measured by using Malvern Zetasizer ZS200. From


the results of all the batches, optimized formulation F8 showed the zeta Drug content
potential at 25 °C was -28.3 mV, zeta potential under ±30 mv shows
good physical stability.19 The Zeta potential of the optimized The drug content was analysed for 10 formulations and the results were
given in Table 2. The drug content of all formulation was found to be
nanosuspension-formulation is given in Figure 4.
in the range of 90.24% to 95.62% and these values are within the
pharma-copoeial limit.

Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017 431


Kumari et al.: Formulation and Evaluation of Meropenam Nano suspension

Figure 4: Zeta potential graph of optimised nanosuspension formulation (F8).

Figure 5: SEM Pictures of meropenem Nanosuspensions.

Entrapment efficiency

The entrapment efficiency of 10 formulations were calculated. The % en-


trapment efficiency of all formulations was found in the range of 52.5%
to 92.6%. Results of particle size, zeta potential, drug content, solubility,
drug content, and entrapment efficiency were shown in Table 2.

In vitro drug release studies and dissolution efficiency

It is evident from the in vitro drug release studies that, pure meropenem
showed 8.6% of drug release at the end of 60 min it may be attributed to its
higher hydrophobic and crystalline nature. Whereas the nanosus-pension
formulations showed more than 50% drug release at the end of 60 min. The
optimized nanosuspension (F8) shows 97.7% drug re-lease at the end of 60
min. The dissolution profiles of the pure drug and nanosuspensions are
shown in the Figure 6. The dissolution efficiency of all the formulations
was calculated. The dissolution efficiency of op-timized formulation was
quite higher (92.6%) when compared to other formulations. From Table 2,
it was found that r2 value of first order was greater than zero order value.
The kinetic profiles of zero and first order
Figure 6: In-vitro dissolution Profiles of meropenem
nanosuspensions and pure form of drug.

432 Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017


Kumari et al.: Formulation and Evaluation of Meropenam Nano suspension
Figure 7: First order and Zero order kinetic plots of meropenem nanosuspensions.

are shown in Figure 7. Hence the drug release from the Stability studies
nanosuspensions followed first order kinetics, correlation coefficient
values of Hixson Crowell model was greater than Higuchi kinetics
The stability study results of nanosuspensions showed that there is no
(Table 2), indicates the drug release follows Hixson Crowell cube root
significant change with respect to the various parameters like particle
kinetics. Hence change in surface area to volume with time could be
size, moisture content, zeta potential, solubility and dissolution before
the probable reasons for increased solubility and dissolution of poorly
and after storage for a period of 6 months as per ICH guidelines. Hence
soluble meropenam on nanonization.20
the nanosuspension are found to be stable at the normal room tempera-
ture.

Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017 433


Kumari et al.: Formulation and Evaluation of Meropenam Nano suspension

Table 1: Formulation of Meropenem Nanosuspensions

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Meropenem (mg) 400 400 400 400 400 400 400 400 400 400

HPMC E-15 (mg) 100 200 300 400 300 300 300 300 300 300

SLS (mg) 50 50 50 50 100 150 200 150 150 150

DCM +Methanol
10 10 10 10 10 10 10 10 10 10
(1:1) (ml)

Time of sonication
15 15 15 15 15 15 15 20 25 30
(min)

Table 2: Evaluation of Meropenem Nanosuspensions

Dissolution
Hixson
Formulation Particle Zeta Solubility Drug content efficiency at 30 First order
% E.E±S.D* Crowell
code size(nm)±S.D* potential(mV)±S.D* (mg/ml)±S.D* (%)±S.D* min (r2 values)
(r2 values)
(%)±S.D*

8±0.4 *n=
Pure drug *n=3 *n=3 3 3 *n=3 32.21 *n=3 *n=3

-
F1 1498±2.1 54.2±0.02 70.2±0.019 52.5±0.03 94.2±0.21 52.1±0.03 0.944 0.965

- 68.42±0.0 90.24±0.0
F2 1251±3.8 42.0±0.13 67.2±0.01 1 6 65.1±0.09 0.985 0.896

- 94.2±0.00
F3 1652 ± 3.8 28.2±1.02 94.2±0.07 78.2±0.41 9 74.2±0.79 0.984 0.972

- 73.82±0.1
F4 501±1.4 32.0±0.01 74.1±0.007 9 90.8±0.09 81.2±0.18 0.988 0.942

- 86.82±0.2 92.55±0.4
F5 400 ±1.6 31.5±0.21 85.52±0.005 3 3 75.1±0.13 0.992 0.965

- 95.21±0.7
F6 102 ± 2.9 28.2±0.05 102.5±0.008 80.2±1.01 9 66.5±0.01 0.994 0.953
- 95.00±0.0
F7 42 ± 2.6 42.5±0.09 94.2±0.012 89.2±1.05 8 56.2±0.82 0.991 0.954

- 95.62±1.0
F8 2.0 ± 3.3 28.3±0.06 128.6±0.016 92.6±0.02 9 92.6±0.23 0.952 0.989

- 88.6±0.00
F9 20 ± 2.8 15.2±0.79 105.5±0.05 9 93.8±0.01 88.2±0.41 0.982 0.978

-
F10 28 ± 1.5 10.5±0.43 120.3±0.015 88.2±0.51 94.2±0.07 86.2±0.12 0.962 0.980

CONCLUSION ACKNOWLEDGEMENT

Emulsification solvent evaporation method was employed in the Authors are thankful to the Aurobindo Pharma ltd., Hyderabad for pro-
prepara-tion of nanosuspensions of meropenem, a poorly soluble drug. viding the meropenem as gift sample and would like to acknowledge
the management of Raghavendra Institute of Pharmaceutical Education
Changing the operation parameters such as sonication time and the
and research for providing the facilities to execute this research work.
concentration of solubilizer and stabilizer, the various nanosuspension
formulations were developed to get the particle size in nano range. The
optimum size range obtained with nanosuspension containing 300 mg CONFLICT OF INTEREST
HPMC E 15, 150 mg SLS for 25 minutes of sonication time. The
solubility and dis-solution of meropenem is significantly increased
compare with the pure drug suspension. The enhanced dissolution of NONE.
drug is due to decreased particle size as well as hydration of drug by
hydrophilic polymer and solubilizer. In conclusion, emulsification
solvent evaporation method is a simple and effective approach to ABBREVIATION USED
produce nanosized particles of poorly water soluble drugs.

BCS: Biopharmaceutical classification System; FTIR: Fourier Trans-

form Infrared; SEM: Scanning Electron Microscopy; DSC: Differential

Scanning Calorimetry; HPMC: Hydroxy Propyl Methyl Cellulose; SLS:

Sodium Lauryl Sulphate; DE: Dissolution Efficiency; AUC: Area Under

the Curve; DCM: Di-Chloro methane; E.E: Entrapment efficiency; S.D:

Standard Deviation.

434 Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017


Kumari et al.: Formulation and Evaluation of Meropenam Nano suspension

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Article History: Submission Date : 18-03-2017; Revised Date : 16-04-2017; Acceptance Date : 28-05-2017.

Cite this article: Kumari SCH, Devi UP, Haritha A, Lava Kumar V, Sowmya C. Solubility and Dissolution Enhancement of Meropenem by Nano Suspension
Approach. J Young Pharm. 2017;9(3):429-35.
Journal of Young Pharmacists, Vol 9, Issue 3, Jul-Sep, 2017 435

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